In:
Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3735-3735
Abstract:
Abstract 3735 Poster Board III-671 Recent clinical trials demonstrated a promising clinical activity of the HDAC inhibitor MGCD0103 in heavily pretreated patients with relapsed HL. However, the mechanisms underlying MGCD0103 activity in HL remains unclear. Here we show that MGCD0103 preferentially inhibited HDACs1, 2 with no effect on HDAC6. Using three HL-derived cell lines, the IC50 for MGCD0103 after 72 hour of incubation was in the submicromolar concentrations, and was more effective than vorinostat in inducing cell death. Using gene expression profiling (GEP) studies, pathway PCR array, and western blot analysis, we identified several pathways that are modulated by MGCD0103. MGCD0103 downregulated the X-linked inhibitor of apoptosis (XIAP) protein, activated the intrinsic caspase pathway, and synergized with TRAIL agonistic antibodies. MGCD0103 downregulated CD30 mRNA and surface protein expression in a dose dependent manner, but had no significant effect on B cell-associated proteins, including CD19 and CD20, or on the costimulatory receptors CD40 and CD80. MGCD0103 induced TNF-alfa expression and secretion, which was associated with NF-kB activation, upregulation of the silencer of cytokine signaling (SOCS)-3, downregulated STAT6, and upregulation of STAT1 and 2. Selective inhibition of TNF-alfa expression by short interfering mRNA enhanced MGCD0103-induced cell death. Similarly, inhibition of NF-kB by proteasome inhibitors also potentiated the effect of MGCD0103, thus demonstrating synergy independent of HDAC6 inhibition. These findings demonstrate that MGCD0103 has a potent anti lymphoma activity by modulating the expression of a variety of survival proteins, and provides mechanistic rationale for combining class-I HDAC inhibitors with proteasome inhibitors and TRAIL. Disclosures: Mamidipudi: Celgene: Employment. Heise:Celgene Corporation: Employment, Equity Ownership. Besterman:Methylgene: Employment. Martell:Methylgene: Employment. MacBeth:Celgene Corporation: Employment, Equity Ownership. Younes:MethylGene: Honoraria, Research Funding.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V114.22.3735.3735
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2009
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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